Esperamicin Golik et al., J. Am. Chem. Soc., 109:3462 (1987)! and calicheamicin Lee et al., J. Am. Chem. Soc., 109:3466 (1987)! are antibiotics that contain a complex bicyclic enediyne allylic trisulfide core structure linked through glycosyl bonds to an oligosaccharide chain. These oligosaccharide chains, in turn, contain a number of substituted sugar derivatives which contain a tetrahydropyran ring substituted on the ring both with a sulfur atom and with the oxygen atom of a hydroxylamine group.
The chemical structures of esperamicin A.sub.I and calicheamicin .gamma..sub.1.sup.I, are illustrated in FIG. 1 herein. The saccharide ring lettered "B" is the aforesaid sulfur- and O-hydroxylamine-substituted tetrahydropyran derivative.
The saccharide rings of an esperamicin correspond to rings "A" and "E" of the calicheamicin shown in FIG. 1 are substituted similarly, except that the esperamicin ring "E" includes an N-isopropyl group rather than an N-ethyl group. The corresponding "B" ring of an esperamicin contains an S-methyl group rather than a S-(saccharide-substituted)-derivatized benzoyl group (C and D rings) shown in FIG. 1. The structures of esperamicin and some of its derivatives are illustrated in U.S. Pat. No. 4,837,206, whose disclosures are incorporated herein by reference.
The enediyne-containing (aglycon or core) and carbohydrate portions of calicheamicin and esperamicin appear to carry out different roles in the biological activity of those molecules. Thus, the core portion appears to cleave DNA Zein et al., Science, 240:1198 (1988)!, whereas the oligosaccharide portion of calicheamicin appears to guide the drug to a double stranded DNA minor groove in which the drug anchors itself on the 5' side of a TCCT sequence, and the core cleaves the DNA. Esperamicins are less sequence specific. Zein et al., Science, 244:697 (1989)!.
Studies of the effect on DNA cleavage of derivatization or removal of one or more of the D and E rings of calicheamicin indicate the following: removal of the E ring (amino sugar) provided a drug with the same DNA cleaving specificity as the parent, but having a DNA-cleaving efficiency 2 to 3 orders of magnitude less; acylation of the E ring amine maintained specificity but lowered efficiency; removal of the D ring (terminal rhamnose) maintained specificity, but lowered efficiency 50-100 times; and removal of the D and E rings (terminal rhamnose and amino sugar) resulted in inhibition of cleaving. Zein et al., Science, 244:697 (1989)!.
Esperamicin lacks the C and D rings but includes a further complex saccharide structure linked to an additional core hydroxyl group. U.K. Patent Application 2,179,649A reports that acid hydrolysis of esperamicins led to cleavage of that second complex saccharide structure and a resulting esperamicin derivative referred to as BBM-1675C that was about as effective as the starting esperamicin BBM-1675A.sub.1 (esperamicin A.sub.1), and more so than esperamicin BBM-1675A.sub.2 (esperamicin A.sub..sub.2) as an antitumor and antimicrobial agent.
U.K. Patent Application 2,179,649A also states that further hydrolysis of esperamicin BBM-1675C led to another esperamicin derivative named BBM-1675D that was also said to be about as effective as esperamicin BBM-1675A.sub.1, as an antitumor and antimicrobial agent. The data presented indicate that esperamicin BBM-1675D possessed only two saccharide rings; i.e. those corresponding to the A and E rings of FIG. 1 herein.
The present invention describes the synthesis of certain key intermediates useful in the preparation of the enediyne core structure for esperamicin or a derivative or an analog thereof.